Seventeen million people each year suffer from an ischemic stroke and millions are left dead and disabled. Treatment with recombinant tissue plasminogen activator (r-tPA) is only modestly effective at reducing disability and it is associated with brain hemorrhage in up to 30% of patients when serial imaging studies are performed. Brain hemorrhage causes death and disability and, is the major cause of early mortality in r-tPA treated patients; there is no proven effective therapy. Stentriever therapy improves reperfusion in ischemic stroke, but it is only available for a minority of patients and it carries a comparable risk of intracranial hemorrhage. A safe treatment for ischemic stroke, used alone or combination with these therapies, which reduces hemorrhage, as well as brain infarction and brain edema could save lives, reduce patient disability and lower health care costs. To address this need, Translational Sciences, Inc. seeks to convert a lead, high-affinity, ultra-specific matrix metalloproteinase-9 inhibitor (MMP-9i) into an optimal therapy for stroke. MMP-9 is a protease induced by ischemia or r-tPA therapy, which degrades the extracellular and the neurovascular matrix. MMP-9 is induced by brain ischemia and by r-tPA therapy; there is abundant evidence that MMP-9 contributes to ischemic brain injury including bleeding during ischemic stroke. Pre-clinical proof-of-concept data, from multiple laboratories, in a number of species and models, shows that inhibiting the action of MMP-9, significantly reduces ischemic brain infarction and disability. Experimental evidence shows that when the lead MMP-9i is added to r-tPA therapy it markedly reduces brain hemorrhage, infarction, swelling, neurobehavioral disability and death in experimental ischemic stroke. Due to its exquisite potency and specificity, this MMP-9i has extraordinary therapeutic potential for reducing morbidity and mortality?without causing the serious adverse events associated with broad spectrum MMP inhibitors. The goal of this Phase I proposal is to follow FDA guidance to convert this potent, specific lead MMP-9i into a humanized, first-in-class therapy for ischemic stroke.